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Cancer Cell. 2018 Jun 11;33(6):1033-1047.e5. doi: 10.1016/j.ccell.2018.05.005.

Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens.

Author information

1
Agenus Inc., Lexington, MA 02421, USA.
2
Agenus Inc., Lexington, MA 02421, USA; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
3
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
4
Agenus Inc., Lexington, MA 02421, USA. Electronic address: david.savitsky@agenusbio.com.
5
Agenus Inc., Lexington, MA 02421, USA. Electronic address: nicholas.wilson@gilead.com.

Abstract

The co-engagement of fragment crystallizable (Fc) gamma receptors (FcγRs) with the Fc region of recombinant immunoglobulin monoclonal antibodies (mAbs) and its contribution to therapeutic activity has been extensively studied. For example, Fc-FcγR interactions have been shown to be important for mAb-directed effector cell activities, as well as mAb-dependent forward signaling into target cells via receptor clustering. Here we identify a function of mAbs targeting T cell-expressed antigens that involves FcγR co-engagement on antigen-presenting cells (APCs). In the case of mAbs targeting CTLA-4 and TIGIT, the interaction with FcγR on APCs enhanced antigen-specific T cell responses and tumoricidal activity. This mechanism extended to an anti-CD45RB mAb, which led to FcγR-dependent regulatory T cell expansion in mice.

KEYWORDS:

CD45RB; CTLA-4; Fc engineering; Fcγ receptor; TCR signaling; TIGIT; cancer immunotherapy; effector T cells; immune synapse; regulatory T cells

PMID:
29894690
PMCID:
PMC6292441
DOI:
10.1016/j.ccell.2018.05.005
[Indexed for MEDLINE]
Free PMC Article

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